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New Cushing’s Saliva Test Does Not Meet Standard Methods


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Context

Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA-F) is a first-line screening test for Cushing’s syndrome (CS) with a reported sensitivity and specificity of >90%. However, liquid chromatography-tandem mass spectrometry, validated to measure salivary cortisol (LCMS-F) and cortisone (LCMS-E), has been proposed to be superior diagnostically.

Objective, Setting, and Main Outcome Measures

Prospectively evaluate the diagnostic performance of EIA-F, LCMS-F, and LCMS-E in 1453 consecutive late-night saliva samples from 705 patients with suspected CS.

Design

Patients grouped by the presence or absence of at least one elevated salivary steroid result and then subdivided by diagnosis.

Results

We identified 283 patients with at least one elevated salivary result; 45 had an established diagnosis of neoplastic hypercortisolism (CS) for which EIA-F had a very high sensitivity (97.5%). LCMS-F and LCMS-E had lower sensitivity but higher specificity than EIA-F. EIA-F had poor sensitivity (31.3%) for ACTH-independent CS (5 patients with at least one and 11 without any elevated salivary result). In patients with Cushing’s disease (CD), most non-elevated LCMS-F results were in patients with persistent/recurrent CD; their EIA-F levels were lower than in patients with newly diagnosed CD.

Conclusions

Since the majority of patients with ≥1 elevated late-night salivary cortisol or cortisone result did not have CS, a single elevated level has poor specificity and positive predictive value. LNSC measured by EIA is a sensitive test for ACTH-dependent Cushing’s syndrome but not for ACTH-independent CS. We suggest that neither LCMS-F nor LCMS-E improves the sensitivity of late-night EIA-F for CS.

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This is a remarkable paper and has big implications for testing and the diagnostic algorithm, especially given who the authors are. The blunt takeaway is do not use salivary cortisol for adrenal Cushing's because it doesn't work. They recommend dex test instead but we know that test has problems too--yes, even in adrenal cases. It's not clear to me if this is generalizable to all mild Cushing's, nor does it appear like cyclical or episodic Cushing's was considered. The other thing is that the technically "better" assay (LCMS) has worse sensitivity than the older, cheaper one (EIA). This is the same thing we saw with the UFC where the older RIAs cross-reacted with cortisol metabolites, so we traded it for the tandem mass spec that produces fewer false positives and more false negatives. I've made all of these points before with my local endo who cited one of the authors of this paper to refute me! 

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